{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T03:11:04Z","timestamp":1788923464019,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Advancements in antisense oligonucleotide (ASO) therapies have expanded their application to neurological disorders through intrathecal (ASO\u2010IT) delivery into cerebrospinal fluid (CSF). To examine study designs and practices in ASO\u2010IT first\u2010in\u2010human (FIH) trials, we analyzed 29 trials between 2010 and 2024 via a comprehensive review. Most trials targeted rare neurological disorders, with increasing numbers of ASO\u2010ITs advancing to clinical testing over time. Patient populations were predominantly used over healthy participants, with over 50% trials employing randomized controlled designs (3:1 active\u2010to\u2010placebo) while others were open label. Trials commonly start in adults or older children before expanding to younger cohorts. Recent trends reveal increased uses of direct\u2010to\u2010multiple ascending dose strategies and single\u2010patient trials, particularly for rare diseases. Dose escalations typically spanned four cohorts over a 10\u00d7 dose range, with early escalations up to 4\u00d7 between adjacent cohorts and smaller increments (1.25\u20101.5\u00d7) in later cohorts. Human dose selection often integrates translational modeling and human equivalent dose approach, scaled by CSF or central nervous system (CNS) tissue volumes. Starting doses prioritized robust safety margins (median 30\u00d7) with limited pharmacological activity, while top doses aimed therapeutic benefit with high activity and safety margins \u22651\u00d7, with the goal to achieve \u226570%\u201080% target engagement (e.g., mRNA knockdown) during dose escalation. Dosing intervals, typically 2\u20104 weeks (up to 12 weeks), reflected ASO\u2010ITs\u2019 prolonged CNS half\u2010life. Adaptive designs enabled real\u2010time dose adjustments upon emerging safety and pharmacokinetics\/pharmacodynamic data. This analysis highlights the importance of flexible, personalized, innovative FIH designs, such as single\u2010patient studies, and model\u2010informed strategies to advance ASO\u2010IT development for rare neurological diseases.<\/jats:p>","DOI":"10.1002\/jcph.70034","type":"journal-article","created":{"date-parts":[[2025,4,21]],"date-time":"2025-04-21T02:52:56Z","timestamp":1745203976000},"page":"1065-1075","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Trends in First\u2010in\u2010Human Studies for Intrathecal Antisense Oligonucleotides: Insights From 2010 to 2024"],"prefix":"10.1002","volume":"65","author":[{"given":"Natalie","family":"Schmitz","sequence":"first","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5102-0162","authenticated-orcid":false,"given":"Mai M.","family":"Abdelmageed","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"},{"name":"Center for Pharmacometrics and Systems Pharmacology College of Pharmacy University of Florida  Orlando FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Monine","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-7131-6288","authenticated-orcid":false,"given":"Yan","family":"Xu","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Pharmacometrics Biogen  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010neuro\u2010070918\u2010050501"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jimd.12251"},{"issue":"10","key":"e_1_2_11_4_1","first-page":"14","article-title":"Fomivirsen approved for CMV retinitis","volume":"4","author":"Roehr B","year":"1998","journal-title":"J Int Assoc Physicians AIDS Care."},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.12.022"},{"issue":"1","key":"e_1_2_11_6_1","first-page":"104","article-title":"Analyzing first\u2010in\u2010human trial designs of antisense oligonucleotides: a preliminary review across subcutaneous, intravenous & intrathecal routes of administration","volume":"13","author":"Abdelmageed M","year":"2024","journal-title":"Clin Pharmacol Drug Dev"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010017\u20100711\u20107"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265\u2010023\u201001904\u20106"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(13)70061\u20109"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/nat.2024.0036"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928\u2010021\u201009761\u20100"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000323"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2015.01.008"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI186116"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2023.114949"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2021.03.002"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpain.2022.900566"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43856\u2010023\u201000419\u20101"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1813279"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.744532"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.3345\/cep.2023.00535"},{"key":"e_1_2_11_22_1","unstructured":"Clinical pharmacology considerations for the development of oligonucleotide therapeutics guidance for industry.US Food and Drug Administration. 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